Harm reduction strategies in acute care for people who use alcohol and/or drugs: A scoping review

Background People who use alcohol and/or drugs (PWUAD) are at higher risk of infectious disease, experiencing stigma, and recurrent hospitalization. Further, they have a higher likelihood of death once hospitalized when compared to people who do not use drugs and/or alcohol. The use of harm reduction strategies within acute care settings has shown promise in alleviating some of the harms experienced by PWUAD. This review aimed to identify and synthesize evidence related to the implementation of harm reduction strategies in acute care settings. Methods A scoping review investigating harm reduction strategies implemented in acute care settings for PWUAD was conducted. A search strategy developed by a JBI-trained specialist was used to search five databases (Medline, Embase, CINAHL, PsychInfo and Scopus). Screening of titles, abstracts and full texts, and data extraction was done in duplicate by two independent reviewers. Discrepancies were resolved by consensus or with a third reviewer. Results were reported narratively and in tables. Both patients and healthcare decision makers contributing to the development of the protocol, article screening, synthesis and feedback of results, and the identification of gaps in the literature. Findings The database search identified 14,580 titles, with 59 studies included in this review. A variety of intervention modalities including pharmacological, decision support, safer consumption, early overdose detection and turning a blind eye were identified. Reported outcome measures related to safer use, managed use, and conditions of use. Reported barriers and enablers to implementation related to system and organizational factors, patient-provider communication, and patient and provider perspectives. Conclusion This review outlines the types of alcohol and/or drug harm reduction strategies, which have been evaluated and/or implemented in acute care settings, the type of outcome measures used in these evaluations and summarizes key barriers and enablers to implementation. This review has the potential to serve as a resource for future harm reduction evaluation and implementation efforts in the context of acute care settings.


Introduction
Substance use is a global health concern, with drug and/or alcohol misuse contributing to over 5% of the global burden of disease [1].People who use alcohol and/or drugs (PWUAD) are at an increased risk of infectious disease, recurring hospitalizations and death [2,3].A recent cross-Canadian study highlighted the increasing potency, unpredictability, and poor quality of unregulated substances placing PWUAD at a greater risk of serious health outcomes, such as poisoning [4].While better management of substance use is recognized as a priority by national and international governing bodies, there are challenges in supporting PWUAD in the health care system.The complex social and health care needs of PWUAD create significant barriers in accessing care [5].A 2010 report from the World Health Organization found that mental health care services, which provide substance use supports, are underutilized by PWUAD [1].In addition to poor access to substance use support across the health and social care system, PWUAD often face stigma when seeking treatment for substance use disorders from health care providers [6].Improved health system supports are urgently needed to ensure all PWUAD receive adequate care.
Harm reduction is an approach that emphasizes working with people where they are at, rather than focusing solely on drug and alcohol abstinence [7].Harm reduction strategies are a promising approach for health care providers and health systems to improve the care of PWUAD.Harm reduction strategies such as safe injection sites, needle exchange programs and methadone maintenance treatment have led to reduced deaths from overdose [8], a decrease in human immunodeficiency virus (HIV) infections [9], and fewer hospitalizations [3].Additionally, the recent decision by the U.S. Department of Health and Human Services' to remove the X-waiver requirement for the use of medication-assisted treatment for people who use opioids highlight that harm reduction strategies are increasingly being viewed as valid and necessary approaches to care [10].Despite advances in our understanding of the effectiveness of harm reduction strategies, greater public buy in, and the need for enhanced access to health care services for PWUAD, there are gaps in how and when PWUAD receive care.
While the majority of harm reduction work for PWUAD has been conducted in the community, evidence suggests that hospitals represent an ideal setting for implementing harm reduction strategies [11].Hospitals are an ideal point of care for PWUAD, with rates of hospital admission and emergency department (ED) utilization higher for PWUAD than the general population [12].In a qualitative study, PWUAD reported that hospital-based harm reduction strategies would enhance patient-centred care by promoting a culturally safe environment, ensuring timely access to care and prioritizing substance use symptoms [2].However, health care providers repeatedly report lack of training as being a barrier to providing quality care to PWUAD in the hospital setting [13].Further, there is little known about how harm reduction strategies are implemented in the inpatient and ED setting, making it challenging to design effective and acceptable interventions for this population.Therefore, the aim of this study is to

Screening approach
Articles retrieved from the search were managed using Covidence [18].Following de-duplication, articles were independently screened by two reviewers, starting with titles and abstracts, and followed by full text papers.Any disagreements between reviewers were resolved through discussion or by consultation with the research team.

Data extraction
Data were extracted from each included study using a predetermined data extraction form.The data extraction form was pilot tested with six team members using one of the included studies.The team met to review any discrepancies in data extraction and to refine the data extraction tool.The data from each study were independently extracted in duplicate.The team met regularly to discuss any concerns related to the data extraction process until data extraction was complete.
Extracted data included characteristic and demographic details such as country, year of publication, study design, objective, participant sample, and setting characteristics.Intervention details included the type and length of intervention, the population targeted by the intervention, what type of drug use the intervention addressed and the reported outcomes measures.Implementation details included whether provider training, sustainability, quality and performance, cost, communication or participant compensation was mentioned.Additionally, data related to reported barriers or enablers to implementation was extracted.

Data synthesis and presentation
Extracted data were synthesized into four major sections (population characteristics, intervention characteristics, characteristics of outcome measures and implementation characteristics) using tables, figures and narrative description.The reporting and presentation of this review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Scoping Reviews (PRISMA-ScR) (S2 Table) [19].
To further elucidate the harm reduction principles present in each intervention approach, the interventions were coded by Hawk et al.'s [20] six harm reduction principles for healthcare settings.These include: humanism, pragmatism, individualism, autonomy, incrementalism and accountability without termination.Interventions which contained pharmacological approaches were coded under pragmatism.Interventions which provided multiple services, tailored their services to meet patient needs and allowed shared decision making in terms of goal setting were coded to individualism.Interventions which supported patients during readmission, provided follow-up and ongoing care and aimed to "meet patients where they are" were coded to incrementalism.Interventions which provided information and/or referrals to additional services and care and allowed patients to make decisions related to their care were coded under autonomy.Interventions which provided education to patients and caregivers related to risks associated with continued drug use and overdose were coded to accountability without termination.Finally, interventions which enacted system changes and emphasized empathy, support, understanding and compassion were coded under humanism.
Barriers and enablers to implementation were organized based on the following pre-defined categories: system and organizational factors, provider-patient communication, patient perceptions and provider perceptions.System and organizational factors encompass barriers/ enablers related to law and policy, funding and resources, and structural and environmental factors such availability of hospital space and the physical location of a hospital.Providerpatient communication encompass barriers/enablers related to communication between providers and patients.Finally, patient perceptions and provider perceptions encompass barrers/ enablers related to how patient and providers perceive the harm reduction strategy.

Patient, decision maker and community organization engagement
Patients and healthcare decision makers were engaged throughout this review to: a) ensure that our research questions aligned with priorities relevant to all partners; b) allow partners with lived experiences of harm reduction programs to contextualize our findings and; c) inform the identification of key gaps in the literature that may have been overlooked without their engagement.
In addition to patients and healthcare decision makers, the preliminary findings of this review were also shared with members of a community organization which provides harm reduction services as part of their community health promotion and disease prevention mandate.Individuals from this organization were given the opportunity to provide feedback and comment on the findings, drawing on their own experiences of receiving, providing and advocating for care.This feedback was used to interpret review findings and integrated into the discussion.Reporting of engagement adhered to the Guidance for Reporting Involvement of Patients and the Public revised short form (GRIPP2-SF) checklist (S3 Table) [21].

Critical appraisal
All studies were critically appraised by two independent reviewers using the Mixed Methods Appraisal Tool (MMAT) [22].The MMAT can be applied to a range of study designs and is therefore useful for scoping reviews.Based on the quality of the report, each article received a score ranging from 0 to 5. Differences in scoring were resolved by consensus or a third reviewer.Scores are listed in Table 1.

Included studies
The database search returned 36,264 records, with 14,580 titles remaining after deduplication.No additional relevant articles were found through the grey literature search.A total of 549 full texts were assessed for eligibility, with 59 studies meeting the inclusion criteria for this review.Our patient partner screened 982 titles and abstracts.An overview of the screening process can be found in
Interventions which targeted patients and caregivers did not report adapting intervention components based on the presence of the caregiver, only that caregivers were welcome to participate in the intervention alongside patients.Interventions which targeted HCP populations primarily utilized education or clinical pathway decision support materials.Only two articles [31,70] utilized policy change as a strategy, and those interventions were targeted at both patient and HCP populations.
Safer consumption approaches included supervised consumption sites (n = 2) [58,67] and needle distribution programs (n = 1) [23].Only one article [61] reported using early overdose protection and the intervention was in the form of an emergency department bathroom sensor that detected when individuals remained immobile for a period of time.Only one article [64] reported utilizing the turning a blind eye approach, which involved ignoring patient drug use at a park across the street from the facility.

Characteristics of outcome measures
Reported outcome measures were organized into four categories, based on those defined by G. Alan Marlatt (1996) and the National Harm Reduction Coalition: [82,83] abstinence, safer use, managed use, and conditions of use and use itself (Table 3).Safer use was comprised of outcome measures related to pharmacological distribution and/or acceptance, syringe acceptance, treatment implementation and presence of safe consumption site.Safer use outcome measures were used most frequently in ED settings.Managed use was comprised of outcome measures related to referral to and/or acceptance of care, satisfaction and/or experience of care and HCP follow-up.Conditions of use and use itself included measures related to mortality, readmission rates, leaving against medical advice (AMA), adverse events, length of stay and frequency of use of drugs and/or alcohol.One article, Schreyer et al., 2020 [61], did not report outcome measures related to these categories, however they did report outcome measures related to implementation.No studies reported on abstinence.

Reported barriers and enablers to implementation
Thirty-eight (64%) of the included articles reported at least one barrier and/or enabler to implementation (Table 4).The most commonly reported barriers and enablers were related to system and organizational factors.Factors related to patient-provider communication, patient perspectives and provider perspectives were also reported.

Partner reflections on gaps in the literature
The following provides additional reflections from our patient and decision maker community partners on gaps identified through our review (Table 5).This section aims to share further contextual details that may be useful to researchers and policy makers.Consultations with partners took place after the preliminary data chart was developed.

Discussion
Overall, this review identified a diverse range of harm reduction strategies, which had been evaluated and implemented in different types of acute health care settings.Strategies were primarily implemented in the ED, followed by a range of inpatient settings such as general medicine, rehabilitation, critical care, and mental health or pain teams.The identified outcome measures used for strategy evaluation were related to safe use, managed use and use itself.
Finally, the included studies did not report detailed implementation strategies or the use of frameworks to guide implementation.Factors related to implementation were inconsistently reported across articles, however a range of barriers and enablers were reported, albeit primarily related to system and organizational level factors.Our findings suggest that there is a growing interest in the implementation of harm reduction strategies within acute care settings, as publications on this subject have dramatically increased within the last three years.While EDs have typically not considered such programs to be part of their mandate, calls for the use of harm reduction strategies within EDs have begun to emerge [84][85][86].This apparent willingness to implement such strategies in ED settings is promising for the success of future projects, particularly given that PWUD seeking health care are more likely to do so via EDs [87].However, while there appears to be growing support within EDs, we identified a limited number of studies which were set in non-mental

System and Organizational Factors: Reported Barriers of Implementation
• Time and labor a burden for HCPs [41,66,70,71,73] • Inadequate training and support for HCPs [48,62,66,69,70,70,81] • Information barrier due to absence of formal guidelines [66] • Staffing issues [29,30,73] • Part-time health educators not available outside working hours [80] • Lack of resources [29,56,62] • Costs associated with implementation [30,50,54,62] • The fast paced nature of the ED, an emphasis on throughput and the constraints of acute care in the ED [53,66] • Referrals were limited by access to specialists, and treatment services in the hospital and the surrounding community [71] • Inadequate administrative support [71] • Difficulty scheduling or locating patients for training.
• Lack of case management when addressing complex psychosocial illnesses [29] • Insurance status [30,66] • Lack of organizational prioritization [70] • Unengaged and remote hospital leadership [70] • Poor interdepartmental communication, collaboration, and coordination [70] • Poor community-hospital partnerships [70] • Absence of local champion [70] • Rural and community hospitals had structural barriers to follow-up treatments [29,32] • COVID 19 initiated closures and decreased intakes to addiction treatment programs creating barriers to care for treatment seeking patients [32] • Screening impacted by patient trauma [80] • Timely identification of patients [62,69] • No systematic approach to selecting clients for program and inability to select clients based on potential future alcohol/drug use [64] • Phones not available in in all treatment areas [81] • Adaptability of intervention [70] • Trained patients forgetting naloxone kits at discharge; only patient who received training used their kits [49,57] • Covering the cost of and sourcing naloxone kits [54,66,70] • Challenges related to documenting the prescribing, dispensing, and training of naloxone distribution [48,53,54,57].
• Inability to dispense naloxone to admitted patients because admitted patients are not permitted to receive discharge medication in the ED prior to transport into the hospital [53] • Ambiguity on dispensing status [66] • Ambiguity on labeling procedures [66] • Ambiguity on legal liability [66] • Obtaining X-waiver to prescribe BUP, and access and availability to MOUD in the community [24,72] • Limited outpatient availability of specialists for OUD [70] • SCS was not designed or equipped to support supervised drug inhalation [67] • SCS was only available to registered inpatients, leaving visitors to use drugs in hospital in unsafe areas [67] • Lack of education and unclear guideline related to MAP [56] System and Organizational Factors: Reported Enablers of Implementation • Brief interventions which require no additional resources to implement [40,76,78] • Securing funding [32,48,66] • Multidisciplinary team involvement including pharmacists, nurses, and practitioners from various specialties [66] • Community organization assistance [66,70] • Pharmacy engagement [66] (Continued ) • Knowledge of state legislation [66] • Collaboration with other surrounding hospitals [66] • Support from hospital leadership; enabling program leaders to address administrative barriers in a timely manner [48,53,66,70] • Full time social workers with low caseloads and a modest discretionary fund [42] • Communication and sharing with local champions and among colleagues [72] • Access to sterile injection supplies and ability to safely disposal of used supplies [67] • Partnerships between pharmacists and physicians [53] • Policy adaptability to local context [70] • Immediate intervention delivery [29,69] • Staff training [35,70] • Adopt protocols to work within the ED setting [32] • Use of trained providers with an awareness of harm reduction principles [32,53] • Empowering clinicians to be "changemakers" reduced the stigma in the hospital and spurred adaptation of health care system to meet patients' needs [32] • Outsourcing SBIR allowed the trauma service to continue to provide high-quality, consistent services [80] • Public pressure to address opioid overdose crisis [70] • Hospital to hospital competition [70] • Public relations pressure to be seen as "taking action" [70] • Regulatory requirements [70] • Provision of state-sponsored training related to OUD medication [70] • Interdepartmental collaboration [70] • Electronic medical record order sets, provider reminders, custom forms, report generation [66,70,73] • Dedicated staff for overdose reporting [70] • Local expertise in addiction medicine [70] • Provider knowledge about OUD and comfort with initiation of OUD medication [39] • Technical assistance [70] • Securing a supply of naloxone kits for dispensing at no cost to the patient [53,66,70] • Leverage the availability of a nonphysician health care provider to provide naloxone education to patients [66] • Protocols for screening patients for naloxone eligibility [53] • Local champions in emergency medicine, social work, psychiatry [70] • Outsourced bilingual health educators who provide direct patient services, record keeping, and information transfer to physicians and nurses [80] Provider-Patient Communication: Reported Barriers of Implementation • Difficulty maintaining contact with providers [64] • Lack of privacy within the ED made patient discussions challenging [69,71] • Difficulty communicating with patient due to language, comprehension, intoxication, and/or altered conscious state [69] • The clients are more likely than others to miss appointments and can be less motivated to reach their full physical potential [64] • Discussing naloxone in a way that encourages patients to buy in [53] • Providers concerned about offending their patients about the cost of naloxone [53] • Patient dishonesty [69] Provider-Patient Communication: Reported Enablers of Implementation • Greater involvement of family members in care/treatment plans and addiction education with nurses and other health care providers [57] • Open discussions with patient and family [62] Patient Perceptions: Reported Barriers of Implementation • Patient apprehension in discussing substance use with HCPs [67,81] (Continued ) health inpatient units.Training and harm reduction programs within these health service settings have the potential to be a valuable resource and reduce stigma.As such, further research exploring implementing programs in non-mental health inpatient settings are needed.
While this review identified a diverse range of harm reduction strategies, additional strategies currently being used in other settings were notably absent.Managing and providing nutrition for PWUAD [88], providing housing resources [89], drug checking technology to allow PWUAD to ascertain unknown chemicals in their street drugs [90,91], and providing off label prescriptions (i.e., safe supply) to PWUAD [92] are all increasingly being considered as • Patient distrust of healthcare services [23,67] • Patient fear of being stigmatized by HCPs [67] • Lack of trust that the hospital SCS would provide adequate protection from criminalization and surveillance [67] Patient Perceptions: Reported Enablers of Implementation • Increased patient awareness of high risk alcohol consumption [69] Provider Perceptions: Reported Barriers of Implementation • Doubt related to policy changes efficacy, screening/treatment efficacy and patient adherence [70,71] • The perception that psychosocial interventions are not the responsibility of ED HCPs [71] • HCP resistance to changes in practice [54,66] • HCP resistance due to belief that they are encouraging drug use and increasing harms [56,66] • HCPs bias and stigma toward drug using patients [54,70,72] • Lack of understanding of who would benefit from naloxone kits [53] • Difficulty motivating HCPs to buy in [57,69,71] • HCP opposition to harm reduction strategies and associated resource allocation [64] Provider Perceptions: Reported Enablers of Implementation • Belief in effectiveness of policy changes [70] • Increased provider awareness of high risk alcohol consumption [69] • Staff acceptance [73] https://doi.org/10.1371/journal.pone.0294804.t004Table 5. Summary of partner reflections on gaps in the literature.

Summary of Partner Reflections on Gaps in the Literature
• Using trauma-informed approaches to guide the design and implementation of harm reduction strategies should be considered.
• PWUAD can experience trauma through interacting with health services and they share these experiences with their peers.Creating and/or improving programs that allow for the reporting of neglect or abuse could help establish greater trust between PWUAD and providers and help improve issues related to accountability.
• Providing education related to safe use of all drugs, not just opioids should be considered when developing harm reduction strategies.
• Providing education to providers on the varied types of drug/alcohol patients may be using and providing education on best practices on how to interact with people who use drugs/alcohol should be considered.
• Treatment referrals are viewed as valuable, but these services can be located away from hospitals, and transit to and from these locations can be viewed as a significant barrier.
• When interacting with healthcare institutions PWUAD can feel like they must critically consider treatment recommendations before they follow them because they may feel that they know more about safe drug use than providers.
• PWUAD often have strong networks and information about safe use practices are often shared within communities.These networks have the potential to be a valuable information sharing resource.
• Future research should consider including PWUAD in the design and implementation of these programs.
• Strategies to deal with adverse events, such as allergic reactions to Naloxone or methadone, should be planned for and integrated into harm reduction programs.https://doi.org/10.1371/journal.pone.0294804.t005important harm reduction approaches, yet to our knowledge they have not been evaluated for use in EDs and/or inpatient settings.Additionally, our patient partners noted that providing education to PWUAD that improves their understanding of the health services they access could help set appropriate expectations on what kind of care they can expect to receive, potentially mitigating instances of leaving against medical advice and/or distrust of HCPs and health services.In the context of other healthcare services, educational strategies focused on health literacy have been shown to strengthen patient engagement [93] and improve patient health outcomes [94] and should therefore be considered as a potential avenue for additional harm reduction approaches.
Most outcome measures included in this review were designed to capture data related to program uptake, adherence and real world efficacy.As such, these outcome measures have the potential to inform the allocation of program resources and the tailoring of programs to specific contexts, making them valuable in informing program implementation, program evaluation and quality improvement projects.Of note, measurement of the satisfaction/experience of care was utilized in only 22% (n = 13) of the included studies.PWUAD dissatisfaction and poor experiences of care has been associated with stigma related to drug use, and this type of stigma has been identified as a factor in increased risk of leaving against medical advice and poor health outcomes [6,95].Additionally, abuse and suffering experienced as a result of accessing healthcare is more likely among stigmatized populations, is poorly understood and often goes unreported [96].Measures of satisfaction or experience of care which are patientoriented could be a valuable tool in widening our understanding of and managing these issues during program implementation and evaluation, potentially leading to improved patient outcomes.
While there were studies included in this review that reported implementation factors related to communication and marketing, cost, quality and performance, sustainability, and provider training, none of the studies utilized validated frameworks to inform their approach to implementation.Given the myriad of factors that can influence effective implementation [97] (e.g., rural/urban setting, available resources, level of personnel training, and patient/provider beliefs and attitudes) a greater emphasis on developing implementation strategies prior to implementation could help improve the effectiveness of approaches.This review also identified a range of barriers and enablers to implementation, most of which related to system and organizational level factors.Absent from these barriers and enablers was public awareness and opinion of harm reduction approaches.Negative public opinion of PWUAD and of harm reduction strategies can negatively impact the perceived value of certain strategies [98].Media reporting of harm reduction services has the potential to reduce stigma against PWUAD and increase acceptance of harm reduction approaches [99].In settings where HCP buy-in is a barrier, utilizing public messaging and information campaigns of the benefits of harm reduction services could help improve uptake by HCPs.

Limitations
We included studies based on our definition of a harm reduction approach.Harm reduction is a broad philosophy encompassing a range of ideas and as such our definition may have limited the inclusion of some approaches.However, our team included a harm reduction specialist who was consulted throughout the process to ensure that we were comprehensive in our inclusion of approaches.This review sought to identify and describe the scope of the available literature and as such providing definitive recommendations related to the implementation and/or evaluation of specific programs was not possible.Further, this review is not a meta-analysis and as such, the generalizability of the results within each study was not assessed.Our approach to data synthesis involved coding extracted data into validated frameworks (e.g., Hawk's harm reduction principles), this process involved some level of subjective interpretation.To mitigate these effects, coding was done independently by two reviewers who then resolved any discrepancies through consensus or consultation with the research team.Our partners were engaged throughout this review to help contextualize our findings and ensure that we maintained a patient-centered approach in our methodology and reporting.Partner reflections should only be considered as potential avenues for future research and not definitive conclusions.

Conclusion
This scoping review sought to map and describe drug and alcohol-related harm reduction strategies, which have been evaluated in inpatient settings and EDs, the outcome measures used to evaluate these strategies, and implementation characteristics.We identified several gaps in the types and targets of potentially beneficial strategies, outcome measures, and factors related to the implementation of harm reduction strategies for PWUAD.Patient partners provided valuable insight throughout the review process to enrich study findings.The findings of this review may inform future research and will serve as a resource for harm reduction evaluation and implementation efforts in the context of EDs and inpatient settings.

Fig 1 (
Preferred Reporting Items for Systematic and Meta Analyses (PRISMA) Flow Diagram).
Support A referral pathway and a referral form to be used by inpatient teams when a patient requires follow-up care postdischarge; skills, and coping with pain.A clinical pharmacy specialist leads a fourth session, providing education regarding MAT for OUD and the role of naloxone rescue kits for overdose.techniques and development of readiness for change-taking an individualized approach to all clients in the spinal cord program.A blind-eye is turned to drug use in an adjacent park.

Table 1 . (Continued) Author, Year Country Setting Study design Study Objectives MMAT Hurt et al., 2020
Evaluate the effect of this new program content (the opioid series) on rates of MAT within 30 days of completion of inpatient rehabilitation with a diagnosis of OUD.Evaluate the effect of MAT and completion of the opioid series was investigated in relation to rates of OUD-related ED visits and/or hospitalization admission within 1 year after rehabilitation program completion ***** Kosteniuk et al., 2021 [67] Canada ED & Inpatient Qualitative Examine key factors that shape patients' decisions to attend or not attend a novel supervised consumption service embedded within a large, urban acute care hospital.***** Ladak et al., 2021 [59] Canada Inpatient-MHA Case Report We present the case of a 40-year-old patient with OUD using illicit fentanyl, heroin, and oxycodone preoperatively and admitted for an elective liver resection for steroid-induced hepatoma.*** Liebling et al., 2021 [52] USA ED & Inpatient Cross Sectional Design (Chart Review) Describe the implementation of hospital-based peer recovery support services for substance use disorder ***** Monti et al., 1999 [44] USA ED RCT Evaluate the use of brief motivational interview to reduce alcohol related consequences and use among adolescents treated in the ER following an alcohol related event *** Moore et al., 2021 [53] USA ED Cross Sectional Design (Chart Review) Evaluate the feasibility of the Point of Care naloxone protocol, and report the rate of obtainment in comparison to previously published references in the literature ***